Abstract

The diverse cytoplasmic domain sequences within the various integrin subunits are critical for integrin-mediated signaling into the cell (outside-in signaling) and for activation of ligand binding affinity (inside-out signaling). Here we introduce an approach based on phage display technology to identify molecules that specifically interact with the cytoplasmic domain of integrins. We show that a peptide selected for binding specifically to the β5 cytoplasmic domain (VVISYSMPD) induces apoptosis upon internalization. The cell death process induced by VVISYSMPD is sensitive to modulation by growth factors and by protein kinase C (PKC), and it cannot be triggered in β5 null cells. Finally, we show that the VVISYSMPD peptide is a mimic of annexin V. Our results suggest a functional link between the αvβ5 integrin, annexin V, and programmed cell death. We propose the term “endothanatos” to designate this phenomenon (Cardo-Vila et al., Molecular Cell, 2003). Novel approaches for antibody generation are being explored in order to map and induce conformational states that trigger endothanatos. We are now also characterizing the functional properties of peptides that associate to the β3 cytoplasmic domain. Further understanding of signaling pathways that regulate cell death and survival may lead to targeted therapies based on selective induction of apoptosis.